While non-insulin dependent diabetes mellitus (NIDDM) is most commonly associated with hyperglycemia and insulin resistance, it is frequently accompanied by a cluster of pathologies, more commonly referred to as the Metabolic Syndrome. The hallmarks of this syndrome are obesity, hypertriglyceridemia, insulin resistance, and hypertension. The high prevalence of these disorders and associated co-morbidities, such as cardiovascular disease and stroke, has lead to increased desire for both preventive care and therapeutic interventions. Current pharmacotherapies for NIDDM range in strategy to include agents that increase insulin secretion, impact insulin action (thiazolidiones, biguanides), alter lipid metabolism (TZD's, fibrates), affect central-feeding behavior, and reduce nutrient absorption (lipase inhibitors). Targeting fructose metabolism offers a novel alternative to current treatment strategies. Recent ecological studies have demonstrated a significant positive correlation between increased energy intake, in the form of highly refined sugars, and the prevalence of both NIDDM and obesity in the U.S. Diets high in fructose have been shown to promote a variety of metabolic disturbances in animal models, including weight gain, hyperlipidemia, hypertension, and insulin resistance. In studies with overweight human subjects, long-term consumption of fructose increased energy intake, body weight, fat mass, blood pressure, and triglyceride (TG) levels. Ingestion of high-fructose diets stimulates de-novo lipogenesis (via up regulation of lipogenic gene expression and activity), shifts the balance between oxidation in favor of re-esterification of fatty acids (FA's), and increases the production of very low density lipoprotein (VLDL) particles. Chronic consumption of diets high in fructose induces elevated levels of free fatty acids (FFA's) and TG's that impair both glucose utilization in muscle tissue and increase the rate of lipolysis in adipose tissue. Fructose-induced TG production may impair insulin-signaling pathways, may be associated with chronic inflammation and may lead to glucolipidtoxicity and can ultimately lead to β-cell failure. Reduction of fructose in the systemic circulation offers the potential to ameliorate the metabolic abnormalities associated with increased fructose consumption and represents a novel therapeutic strategy to treat both NIDDM and Metabolic Syndrome.
Fructose is readily absorbed from the diet and is metabolized rapidly in the liver. Fructokinase, also known as ketohexokinase, is the hepatic enzyme that phosphorylates fructose to fructose-1-phosphate and serves as the entry point of this sugar into the metabolic pathway. In contrast to the highly regulated process of glucose metabolism, fructose metabolism lacks similar control mechanisms. For example, fructokinase has a high KM value, is not inhibited by product, and is not allosterically regulated. Consequently, high concentrations of fructose can rapidly flux into glycolytic pathways and provide both the glycerol and acyl components of triglycerides (TG). Thus, the metabolism of fructose provides a relatively unregulated source of carbon substrates that promotes TG synthesis and underlies a variety of metabolic disorders. Human genetic validation of this target is supported by the discovery of mutations that cause the autosomal recessive disorder essential fructosuria. Individuals with this benign condition have inactive isoforms of hepatic fructokinase. Upon ingestion of fructose, sucrose, or sorbitol, affected individuals exhibit a significant and persistent rise in blood fructose concentrations, and excrete part of the load in the urine. This supports the rationale that a fructokinase inhibitor would spill excess carbohydrate into the urine with a significant margin of safety. This approach represents a novel therapeutic strategy to reduce body weight, FFA's and TG levels, and serve the unmet needs of both NIDDM and Metabolic Syndrome.